Loss-of-function mutations in AKAP11 (a protein kinase A (PKA)-binding protein) greatlyincrease the risk of bipolar disorder and schizophrenia. To determine the neurobiologicalfunctions of AKAP11, we conduct multi-omic and neurobiological analyses of Akap11 mutantmouse brains. We find that AKAP11 is a key regulator of PKA proteostasis in the brain whoseloss leads to dramatically increased levels of PKA subunits and phosphorylated PKA substrates,especially in synapses. Akap11 mutant mice show extensive transcriptomic changes throughoutthe brain, including prominent decreases in synapse-related genes sets. Gene expression is highlyimpacted in spiny projection neurons of the striatum, a brain region implicated in motivation,cognition and psychotic disorders. Real-time measurements of PKA activity reveal elevatedbasal PKA activity in striatum of Akap11 38 -/- mice, with exaggerated additional response todopamine receptor antagonists. Behaviorally, Akap11 mutant mice show abnormally prolongedlocomotor response to amphetamine, deficits in associative learning and contextualdiscrimination, as well as depression-like behaviors. Our study connects molecular changes tocircuit dysfunction and behavioral disturbance in a genetically valid animal model of psychoticdisorder.